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. Author manuscript; available in PMC: 2024 Dec 1.
Published in final edited form as: JAMA Dermatol. 2023 Dec 1;159(12):1373–1382. doi: 10.1001/jamadermatol.2023.3949

Safety and Effectiveness of Oral Nutraceuticals for Treating Acne

A Systematic Review

Ali Shields 1, Sophia Ly 2, Bruna Wafae 3, Yu-Feng Chang 4, Priya Manjaly 5, Marjorie Archila 6, Christina Heinrich 7, Lara Drake 8, Arash Mostaghimi 9, John S Barbieri 10
PMCID: PMC11015159  NIHMSID: NIHMS1983923  PMID: 37878272

Abstract

IMPORTANCE

Patients with acne are interested in nutraceuticals as a potential treatment option. However, there is uncertainty regarding the efficacy and safety of these products.

OBJECTIVE

To evaluate the evidence for oral nutraceuticals in the treatment of acne.

EVIDENCE REVIEW

The PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science databases were searched from inception through January 30, 2023, to identify randomized clinical trials evaluating oral nutraceutical interventions (ie, vitamins and minerals, botanical extracts, prebiotics, and probiotics) in individuals with acne. Clinician-reported outcomes (eg, investigator global assessment, lesion counts), patient-reported outcomes (eg, quality of life), and adverse events were extracted from the included studies. The quality of evidence was assessed using the Cochrane Risk of Bias checklist tool for randomized clinical trials. Based on the Risk of Bias tool, articles were converted to Agency for Healthcare Research and Quality standards of good, fair, or poor quality.

FINDINGS

A total of 2582 abstracts were identified in the database search, 42 of which met inclusion criteria (a total of 3346 participants). Studies of fair or good quality showed the potential benefit of vitamins B5 and D, botanical extracts (green tea), probiotics, and ω-3 fatty acids in the treatment of acne. These interventions were most frequently associated with decreased lesion counts or improved investigator global assessment scores. Adverse effects were rare for most of the therapies evaluated, but gastrointestinal tract adverse effects were reported for zinc therapy.

CONCLUSIONS AND RELEVANCE

This systematic review suggests a possible role for nutraceutical supplements in the treatment of acne. Physicians should be prepared to discuss the evidence regarding the potential role of nutraceuticals with patients. Many studies were of small size, and future research should focus on larger randomized clinical trials to assess the utility of nutraceuticals in the treatment of acne.

While many topical and systemic prescription options are available for the treatment of acne, some patients may be interested in natural and complementary therapies as either an adjunctive or an alternative to prescription medications.1 Nutraceuticals are products derived from food sources that provide both nutritional and medicinal benefits. These can include vitamins, dietary supplements, and herbal products. Although patients may be interested in nutraceuticals as a potential treatment option for acne, there is uncertainty regarding the efficacy and safety of these products. Given the frequency of nutraceutical use among patients with acne, we aimed to evaluate the data behind the use of oral nutraceuticals in the management of acne.

Methods

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. As the study only uses publicly available data (published articles), it was deemed exempt by the investigators and not reviewed by an institutional review board. The study was registered with PROSPERO (CRD42022353051).

Information Sources and Search

A health sciences librarian (C.H.) performed a search of the PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science databases from inception through August 16, 2022. The search was subsequently updated through January 30, 2023. The strategy combined 2 concepts, acne vulgaris and nutraceuticals, using keywords and subject headings when available for each. The Cochrane limit for studies in humans and the Cochrane highly sensitive search strategy for identifying randomized trials in PubMed, Embase, and the Cochrane Central Register of Controlled Trials were applied.2 An unvalidated filter was used in the Web of Science to identify randomized clinical trials in humans.3 The full search strategy is available in the eMethods in the Supplement.

Eligibility Criteria

We included randomized clinical trials investigating at least 1 oral nutraceutical in patients with acne vulgaris compared with placebo or other active therapies. Systematic reviews and conference abstracts or presentations were excluded. Outcomes of interest were Investigator Global Assessment of Acne (IGA) or clinician-reported improvement, lesion count, patient satisfaction or patient-reported outcome measures, and adverse events.

Study Selection, Data Extraction, and Quality Assessment

At least 2 reviewers independently screened the titles and abstracts of each retrieved record and reviewed the full text of each eligible study using the Rayyan systematic review software4 (including A.S., S.L., B.W., Y.-F.C., P.M., and M.A.). Any discrepancies were mediated by a third reviewer (J.S.B.). For each of the included articles, study design, nutritional intervention, and outcomes were reviewed. Quality assessment of included trials was performed using the Cochrane Risk of Bias checklist tool.5 Based on this tool, articles were categorized according to the Agency for Healthcare Research and Quality standards of poor, fair, or good quality (Table 1 and Table 2), with this review focusing on studies of at least fair quality. Good-quality studies met all criteria or had a low risk of bias for each domain. Fair-quality studies either had 1 criterion not met (ie, high risk of bias for 1 domain) or 2 criteria unclear. Poor-quality studies had 2 or more criteria listed as high or unclear risk of bias and assessment that this was likely to have biased the outcome.

Table 1.

Effectiveness of Evaluated Nutraceuticals by Quality Level of Study

Quality levela Nutraceutical No. of studies
Study supports potential effectiveness Study does not support effectiveness
Poor Zinc 4 5
Vitamin A 0 1
Vitamin C 1b 0
Vitamin D (alfacalcidol) 1b 0
Emblica officinalis (amalaki) extract 1 0
Mangosteen rind extract 0 1
Gugulipid extract 0 1
Trenev Trio (Natren) and/or Healthy Trinity (Natren) 1 0
γ-Linolenic, linoleic, and oleic acids 0 1
Coenzyme Q10 1b 0
Soybean isoflavone 2 0
Lactium (Ingredia) 0 1
Keigairengyoto 0 1
Zinc, lactoferrin, vitamin E 1 0
Probiotic blend plus botanical extract blend 1 0
Seboguard oral (Cantabria Labs Difa Cooper) 1 0
Gender-based oral supplement 1 0
Linoleic acid, palmitoleic acid, magnesium phosphate 1 0
Fair Zinc 4 2
Pantothenic acid (vitamin B5) 1 0
Fenugreek seed extract 1
Eximia Probiac (Melora) 1 0
Lactobacillus rhamnosus SP1 1 0
γ-Linoleic acid (borage oil) 1 0
ω-3 Fatty acids (EPA or DHA) 1 0
Good Vitamin D (cholecalciferol) 1 0
Green tea extract 1 0
Lactobacillus plantarum 1 0
Cheongsangbangpoong-tang 1 0
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Abbreviations:

DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.

a

Quality defined by converting the Cochrane Risk of Bias tool to Agency for Healthcare Research and Quality standards. Good quality indicates all criteria met (ie, low for each domain); fair quality, 1 criterion not met (ie, high risk of bias for 1 domain) or 2 criteria unclear; and poor quality, 2 or more criteria listed as high or unclear risk of bias and assessment that this was likely to have biased the outcome. Demonstrated potential effectiveness defined as statistically significant difference (P < .05) between intervention and comparator groups in favor of intervention for at least 1 outcome.

b

Only commented on within-group differences (improvement from baseline), not between groups.

Table 2.

Cochrane Risk of Bias Assessment

Source Nutraceutical Risk of bias assessed
Random sequence generation Allocation concealment Selective reporting Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Quality
Zinc
Hillström et al,6 1977 Zinc sulfate Unclear Unclear High Low Low Low Poor
Orris et al,7 1978 Zinc sulfate Unclear Low Low Low Unclear Unclear Poor
Agrawal et al,8 1985 Zinc sulfate Unclear Low Low Low Unclear Low Fair
Michaëlsson et al,9 1977 Zinc sulfate Low High Low High High Low Poor
Göransson et al,10 1978 Zinc sulfate Low Unclear Low Low Low Low Fair
Verma et al,11 1980 Zinc sulfate Unclear Unclear Low Low Low Low Fair
Weisman et al,12 1977 Zinc sulfate Unclear Low Low Low Unclear High Poor
Weimar et al,13 1978 Zinc sulfate Low Unclear Low Low Unclear Unclear Poor
Dreno et al,14 1989 Zinc gluconate Low Low Low Low Unclear Low Fair
Lim-Ang et al,15 2021 Zinc gluconate Unclear Unclear Low Low Low Low Fair
Meynadier,16 2000 Zinc gluconate Low Unclear Low Low Unclear Low Fair
Tolino et al,17 2021 Zinc sulfate Low Unclear Low High High Low Poor
Michaëlsson et al,18 1977 Zinc sulfate Unclear Low Low Low Unclear Low Fair
Cunliffe et al,19 1979 Zinc sulfate and/or zinc citrate Unclear Unclear Low Low Unclear Low Poor
Dreno et al,20 2001 Zinc gluconate Unclear Unclear Low Low Unclear Low Poor
Vitamins
Anderson and Stokoe,21 1963 Vitamin A Unclear Unclear Low Low High High Poor
Yang et al,22 2014 Pantothenic acid (vitamin B5) Low Unclear Low Low Unclear Low Fair
Shubber et al,23 2020 Vitamin C, doxycycline hyclate Unclear Unclear Low High High Low Poor
Mohamed et al,24 2021 Vitamin D Unclear Unclear High High Unclear Low Poor
Lim et al,25 2016 Vitamin D Low Low Low Low Low Low Good
Botanical extracts
Lu and Hsu,26 2016 Green tea extract Low Low Low Low Low Low Good
Patel et al,27 2021 Emblica officinalis (amalaki) extract Unclear Unclear Low Unclear High Low Poor
Sepaskhah et al,28 2019 Fenugreek seed extract Low Low Low Low Low Unclear Fair
Sutono,29 2013 Mangosteen rind extract Unclear Unclear Low Low Unclear Low Poor
Thappa and Dogra,30 1994 Gugulipid extract Unclear Unclear Unclear High High Unclear Poor
Probiotics
Dias da Rocha et al,31 2022 Eximia Probiac (Melora) Unclear Unclear Low Low Low Low Fair
Jung et al,32 2013 Trenev Trio (Natren) and/or Healthy Trinity (Natren) Low High Low High Low Low Poor
Kim et al,33 2021 Lactobacillus plantarum Low Low Low Low Low Low Good
Fabbrocini et al,34 2016 Lactobacillus rhamnosus SP1 Low Unclear Low Low Unclear Low Fair
Fatty acids
Jung et al,35 2014 ω-3 fatty acid and/or γ-linoleic acid Low Low Low Unclear Low Low Fair
Prati et al,36 2022 Dietary fatty acids Unclear Unclear Low High High Low Poor
Other supplements
Adriana et al,37 2021 Coenzyme Q10 Unclear Unclear Low Unclear Unclear Low Poor
Riyanto et al,38 2015 Soybean isoflavone Unclear Unclear Low Low Unclear Low Poor
Riyanto and Subchan,39 2015 Soybean isoflavone Unclear Unclear Low Low Unclear Low Poor
Kerure et al,40 2022 Lactium (Ingredia) Low Low Low High High Low Poor
Kim et al,41 2019 Cheongsangbangpoong-tang Low Low Low Low Low Low Good
Ito et al,42 2018 Keigairengyoto Unclear Unclear High High High High Poor
Multi-ingredient supplements
Chan et al,43 2017 Zinc gluconate, lactoferrin, vitamin E Unclear Unclear High Low Unclear Low Poor
Rinaldi et al,44 2022 Probiotic blend plus botanical extract blend Unclear Unclear Low Low Unclear Low Poor
Kazandjieva et al,45 2022 Seboguard oral (Cantabria Labs Difa Cooper) Low Unclear Low High Low Low Poor
de Souza Pereira,46 2023 Dietary fatty acid supplement Low Unclear Unclear High High Unclear Poor
Tolino et al,47 2018 Gender-based oral supplement Unclear Unclear Low Low Unclear Low Poor
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Results

The search yielded 2582 records. Of these, 2489 records were excluded based on title and abstract screening. Among 93 full-text articles assessed for eligibility, 42 articles (3346 participants)6–24,26–47 met the inclusion criteria and were included in the review (Figure). Of the included studies, 27 (64.3%)6,7,9,12,13,17,19–21,23,24,27,29,30,32, 36–40, 42–47 were of poor quality, 11 (26.2%)8,10,11,14–16,18,22,28,31,34,35 were of fair quality, and 4 (9.5%)25,26,33,41 were of good quality (Table 1, Table 2, and Table 3). Detailed information on the included studies, including for poor-quality studies, is available in the eTable in the Supplement.

Figure.

Figure.

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Study Flow Diagram

CENTRAL indicates Cochrane Central Register of Controlled Trials.

Table 3.

Characteristics of Included Studies

Study Nutraceutical (No. of patients) Ingredients Dosage Additional therapy (used in all groups) Comparator (No. of patients) Length of intervention
Zinc
Hillström et al,6 1977 Zinc sulfate (48) Effervescent tablets of zinc sulfate 400 mg/d NA Placebo (43) 12 wk
Orris et al,7 1978 Zinc sulfate (12) Effervescent tablets of zinc sulfate 411 mg/d NA Placebo (10) 8 wk
Agrawal et al,8 1985 Zinc sulfate (17) Capsules of zinc sulfate 440 mg/d NA Placebo (18) 12 wk
Michaëlsson et al,9 1977 Zinc sulfate (15) Effervescent tablets of zinc sulfate 600 mg/d NA Placebo (14) 4–12 wk
Göransson et al,10 1978 Zinc sulfate (27) Effervescent tablets of zinc sulfate 600 mg/d NA Placebo (25) 6 wk
Verma et al,11 1980 Zinc sulfate (29) Capsules of zinc sulfate 600 mg/d NA Placebo (27) 12 wk
Weisman et al,12 1977 Zinc sulfate (20) Effervescent tablets of zinc sulfate 600 mg/d NA Placebo (19) 12 wk
Weimar et al,13 1978 Zinc sulfate (18) Capsules of zinc sulfate 660 mg/d NA Placebo (22) 12 wk
Dreno et al,14 1989 Zinc gluconate (32) Capsules of zinc gluconate 200 mg/d NA Placebo (34) 8 wk
Lim-Ang et al,15 2021 Zinc gluconate (8) Capsules of zinc gluconate 200 mg/d Adapalene, 0.3%; benzoyl peroxide gel, 2.5% Placebo (8) 8 wk
Meynadier,16 2000 Zinc gluconate (32) Capsules of zinc gluconate 400 mg/d For 3 wk, followed by 200 mg/d for 4 wk, followed by 100 mg/d for 6 wk NA Constant dose of zinc gluconate (200 mg/d) (35) 13 wk
Tolino et al,17 2021 Zinc sulfate (50) Oral tablets of zinc sulfate 400 mg/d NA Lymecycline (300 mg/d) (50) 12 wk
Michaëlsson et al,18 1977 Zinc sulfate (19) Effervescent tablets of zinc sulfate 600 mg/d NA Oxytetracycline hydrochloride (250 mg/d) (18) 12 wk
Cunliffe et al,19 1979 Zinc sulfate and/or zinc citrate (20) Capsules of zinc sulfate and zinc citrate complex 3 Capsules/d NA Tetracycline hydrochloride (500 mg/d) (20) 12 wk
Dreno et al,20 2001 Zinc gluconate (163) Capsules of zinc gluconate 200 mg/d NA Minocycline hydrochoride (100 mg/d) (169) 12 wk
Vitamins
Anderson and Stokoe,21 1963 Vitamin A (30) NA 150 000 IU/d NA Placebo (31) 12 wk
Yang et al,22 2014 Pantothenic acid (vitamin B5) (20) Tablets of pantothenic acid 2.2 g/d NA Placebo (21) 12 wk
Shubber et al,23 2020 Vitamin C, doxycycline hyclate (15) Chewable vitamin C tablets 500 mg/d NA Doxycycline hyclate (100 mg/d) (15) 4 wk
Mohamed et al,24 2021 Vitamin D (50) Alfacalcidol 0.25 μg/d NA Placebo (50) 12 wk
Lim et al,25 2016 Vitamin D (20) Cholecalciferol 1000 IU/d NA Placebo (19) 8 wk
Botanical extracts
Lu and Hsu,26 2016 Green tea extract (33) Capsules of green tea extract 1500 mg/d NA Placebo (31) 4 wk
Patel et al,27 2021 Emblica officinalis (amalaki) extract (12) Capsules of amalaki extract 500 mg/d NA Placebo (12) 8 wk
Sepaskhah et al,28 2019 Fenugreek seed extract (8) Capsules of hydroalcoholic extract of fenugreek seeds 500 mg/d NA Azithromycin (125 mg/d) (6) 8 wk
Sutono,29 2013 Mangosteen rind extract (45) Capsules of mangosteen rind extract 1200 mg/d NA Placebo (40) 3 wk
Thappa and Dogra,30 1994 Gugulipid extract (10) Tablets of gugulipid containing active guggulsterone 50 mg/d NA Tetracycline hydrochloride (500 mg/d) (10) 12 wk
Probiotics
Dias da Rocha et al,31 2022 Eximia Probiac (Melora) (107) Lactobacillus acidophilus Not provided Topical adapalene, 0.1%; benzoyl peroxide gel, 2.5% Placebo (105) 26 wk
Bifidobacterium lactis
Jung et al,32 2013 Trenev Trio (Natren) and/or Healthy Trinity (Natren) (15) Lactobacillus acidophilus 6.0 × 109 CFU NA Minocycline hydrochloride (13) 12 wk
Lactobacillus delbrueckii 5.0 × 109 CFU
Bifidobacterium bifidum 2.0 × 1010 CFU
Kim et al,33 2021 CJLP55 (14) Lactobacillus plantarum 1.0 × 1010 CFU NA Placebo (14) 12 wk
Fabbrocini et al,34 2016 LSP1 (10) Lactobacillus rhamnosus SP1 3.0 × 109 CFU NA Placebo (10) 12 wk
Fatty acids
Jung et al,35 2014 ω-3 (15) and γ-Linoleic acid (15) ω-3 Fatty acids: eicosapentaenoic acid and/or doxosahexaenoic acid 2000 mg/d NA Placebo (15) 10 wk
γ-Linolenic acid: borage oil 400 mg/d
Jung et al,35 2014 Dietary fatty acids (13) γ-Linolenic acid 480 mg/d NA Lymecycline (300 mg/d) (11) 13 wk
Linoleic acid 1200 mg/d
Oleic acid 510 mg/d
Other supplements
Adriana et al,37 2021 Coenzyme Q10 (18) Tablet of coenzym Q10 100 mg/d Tretinoin cream, 0.025% Placebo (18) 8 wk
Riyanto et al,38 2015 Soybean isoflavone (20) Capsules of soybean isoflavone 160 mg/d Tretinoin cream, 0.025% Placebo (20) 12 wk
Riyanto and Subchan,39 2015 Soybean isoflavone (5/group) Capsules of soybean isoflavones 40 mg/d Tretinoin cream, 0.025% Placebo (5) 4 wk
80 mg/d
120 mg/d
160 mg/d
Kerure et al,40 2022 Lactium (Ingredia) (45) Capsules of αS1-casein tryptic hydrolysate 150 mg/d Oral doxycycline hyclate, adapalene, clindamycin gel Placebo (40) 12 wk
Kim et al,41 2019 Cheongsangbangpoong-tang (28) Cheongacsangbangpoongtang extract granules 15 g/d NA Placebo (28) 8 wk
Ito et al,42 2018 Keigairengyoto (29) Keigairengyoto extract granules 15–22.5 g/d Adapalene, 0.1%; topical antimicrobial agent Placebo (29) 12 wk
Multi-ingredient supplements
Chan et al,43 2017 Zinc gluconate, lactoferrin, vitamin E (82) Zinc gluconate 33 mg/d NA Placebo (82) 12 wk
Lactoferrin 100 mg/d
Vitamin E as α-tocopherol 11 IU/d
Rinaldi et al,44 2022 Probiotic blend (27) Bifidobacterium breve 5.0 × 108 CFU NA Placebo (28) 8 wk
Lacticaseibacillus casei 5.0 × 108 CFU
Ligilactobacillus salivarius 1.0 × 109 CFU
Botanical extract blend (29) Lupeol Not provided
Echinacea
Kazandjieva et al,45 2022 Seboguard oral (Cantabria Labs Difa Cooper) (61) Prebiotic blend (fructose and galactose oligosaccharides) Not provided Seboguard topical cream (Cantabria Labs Difa Cooper): hydroxypinacolone retinoate, retinyl palmitate, Iris florentina root extract, oligopeptide complex Placebo (123) 12 wk
Zinc
Lactoferrin
Niacinamide
de Souza Pereira,46 2023 Dietary fatty acid supplement Linoleic acid 100 mg/d NA Isotretinoin (0.5–1.0 mg/kg/d) 26 wk
Palmitoleic acid 100 mg/d
Magnesium phosphate 100 mg/d
Tolino et al,47 2018 Female gender-based oral supplement (60) Biotin Not provided Topical therapy: salicylic acid, gluconolactone, verbascoside, Ocimum gratissimum Placebo (60 female, 60 male) 12 wk
Probiotic
Vitamin E
Zinc
Nicotinamide
Myo-inositol
Folic acid
Male gender-based oral supplement (60) Biotin
Probiotic
Vitamin E
Zinc
Nicotinamide
β-Sitosterol
Boswellia serrata
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Abbreviations: CFU, colony-forming units; CJLP55 Lactobacillus plantarum; LSP1, Lactobactillus rhomnosus SP 1; NA, not applicable.

Zinc

Zinc is thought to target acne through decreasing sebum production and anti-inflammatory mediators as well as through antibacterial effects on Cutibacterium acnes, though its exact mechanisms are not fully understood.48 Of the 15 articles evaluating zinc in the treatment of acne,6–20 4 of 6 studies (66.7%) of fair quality10,11,14,16 and 4 of 9 studies (44.4%) of poor quality6,9,13,17 found zinc to be efficacious (Tables 1–3 and eTable in the Supplement).

Zinc Sulfate

In a 12-week double-blind trial of 35 patients, Agrawal et al8 assessed the effectiveness of zinc sulfate (440mg/d) vs placebo and found no significant difference in the groups before and after treatment regarding subjective improvement (47.1% vs 38.9%;P > .05).There was not a statistically significant difference in change in mean (SD) severity score (42.5 [20.8] vs 43.5 [40.8]; P > .05) between the groups.

At higher doses of zinc sulfate (600 mg/d), 2 studies10,11 found superiority to placebo. In a 6-week double-blind investigation of 54 patients treated with zinc sulfate (600 mg/d) or placebo, Göransson et al10 demonstrated a significant difference in favor of the zinc group regarding improvement in total number of lesions (21.9 vs 18.9; P = .03), acne scores (18.8 vs 10.8; P = .01), and percentage change in scores (33.4% vs 18.3%; P = .007). There was no significant difference in the rates of subjective improvement (37% vs 19% with improvement; P > .05). Improvement of acne with zinc sulfate (600 mg/d) compared with placebo was demonstrated in another double-blind trial of 56 patients by Verma et al.11 Of the 29 patients receiving zinc sulfate, 14 showed some improvement (3 excellent, 10 moderate, and 1 slight) after 6 weeks of treatment, while patients in the placebo group either showed no improvement or aggravation of their acne. In the zinc-treated group, there was also a statistically significant decrease in the number of papules (mean [SD], 29.38 [12.50] to 7.41 [4.61]), infiltrates (mean [SD], 1.65 [2.89] to 0.29 [1.17]), and cysts (mean [SD]. 0.52 [1.58] to 0.48 [0.47]) compared with baseline (P < .05).

Zinc Gluconate

Two studies14,16 demonstrated improvement in patients treated with zinc gluconate (200 mg/d). In a double-blind trial of 66 patients, Dreno et al14 found zinc gluconate led to greater clinician-reported improvement (75% vs 23.5%; P < .001) and patient-reported improvement (62.5% vs 35.3%; P < .002) after 8 weeks compared with placebo. In a double-blind trial of 67 patients, Meynadier16 compared a loading dose of zinc gluconate (400 mg/d for 3 weeks) followed by normal doses (200 mg/d for 4 weeks and 100 mg/d for 6 weeks) to the conventional therapeutic regimen for zinc gluconate (200 mg/d) for 13 weeks. The loading dose of zinc gluconate (no data, 11.4%; worsening, 22.9%; stationary, 11.4%; slight improvement, 20.0%; marked improvement, 34.3%) was no more effective than 200 mg/d dose (no data, 12.5%; worsening, 12.5%; stationary, 12.5%; slight improvement, 21.9%; marked improvement, 40.6% [P = .74]), favoring the conventional therapeutic regimen.

Zinc vs Active Comparator

In a double-blind trial of 37 patients treated with zinc sulfate (600 mg/d) or oxytetracycline, Michaëlsson et al18 discovered no significant difference in lesion counts and clinician global assessment (P > .05) after 12 weeks. The reduction in the total number of lesions was 58.2% in the zinc-treated group and 63.3% in the oxytetracycline-treated group, while the rating of improvement was 1.6 for the zinc group and 1.8 for the oxytetracycline group.

Summary

Zinc was the most studied nutraceutical identified in this review; however, there was substantial heterogeneity in the results, with only slightly greater than one-half of studies finding zinc to be efficacious. Studies using higher doses more often found zinc to be efficacious. Zinc had the highest rate of adverse effect reporting of any nutraceuticals assessed in this review. In most of the included studies,6–20 participants reported gastrointestinal tract adverse effects (ie, nausea, vomiting, abdominalpain, indigestion). In the studies wherein zinc was compared with antibiotics,17–20 the rate of gastrointestinal tract adverse effects was similar between the groups.

Vitamins

Vitamin A

Prior to the approval of isotretinoin, vitamin A was used as an acne treatment. Similar to isotretinoin, vitamin A addresses pathogenic factors that contribute to the development of acne by decreasing sebaceous gland activity and inhibiting comedogenesis. However, randomized clinical trials to support the role of vitamin A in the treatment of acne are generally lacking, with much of the evidence base consisting of case reports and small case series published over 60 years ago.49 In a 12-week placebo-controlled trial, Anderson and Stokoe21 found that clinician-assessed improvement and improvement based on photographs judged by a panel were equivalent between vitamin A (150 000 IU/d) and placebo. Though no adverse effects were reported in this trial, vitamin A has the potential for teratogenicity, neuropsychiatric disturbances, and mucocutaneous adverse effects; the high doses required for acne therapy increase the likelihood of developing these adverse effects.49

Vitamin B5 (Pantothenic Acid)

Pantothenic acid (vitamin B5) is thought to have a role in the treatment of acne due to its effect on regulating epidermal barrier function and keratinocyte differentiation via coenzyme A metabolism.50 In a 12-week double-blind trial of 41 patients with acne, Yang et al22 found a supplement containing pantothenic acid (2.2 g/d) to be superior to placebo in terms of reduction of total facial lesions (68.2% greater reduction with pantothenic acid; P = .02) and improvement in Dermatology Life Quality Index scores (1.93 vs 5.3 at week 12; P = .02 [0 indicates lowest disease severity; 30 indicates greatest disease severity]). In addition, those in the pantothenic acid group were significantly more likely to achieve IGA success, defined as improvement to grade 1 or lower (42.9% vs 14.3%; P = .04).No adverse events related to the study agent were reported during the study period.

Vitamin D

There has been interest in exploring vitamin D as a treatment for acne, given the potential role of vitamin D in modulating the immune response and based on observational data that patients with acne may be more likely to have a vitamin D deficiency.51,52 In a double-blind trial of 39 patients with vitamin D deficiency, Lim et al25 found vitamin D supplementation (1000 IU/d of cholecalciferol) led to a significantly greater reduction of inflammatory lesions compared with placebo (34.6% vs 5.8%; P < .05) after 8 weeks of treatment. However, no significant differences in the noninflammatory and total lesion counts were found between the groups. No adverse events were reported with supplementation of vitamin D.

Botanical Extracts

Green Tea Extract

Epigallocatechin-3-gallate, the major polyphenol in green tea, has anti-inflammatory and antimicrobial activities that could modulate several key pathological factors of acne.53 In a double-blind trial of 64 women with postadolescent acne, Lu and Hsu26 found decaffeinated green tea extract (1500 mg/d) led to greater reduction in inflammatory lesion counts of the nose (1.0 vs 1.5; P = .03), perioral area (1.7 vs 2.7; P = .04), and chin (2.3 vs 3.7; P = .03) compared with placebo following 4 weeks of treatment. However, no significant difference was found in the Cardiff Acne Disability Index scores between the groups (4.7 vs 4.9; P = .83 [0 indicates lowest disease severity; 15 indicates greatest disease severity]). One participant developed mild constipation and 2 others had abdominal discomfort in the green tea extract group.

Fenugreek Seed Extract

Fenugreek seed extract is thought to have antioxidant effects due to its high concentration of polyphenol compounds.54 In a triple-blind study of 20 patients with acne, Sepaskhah et al28 compared fenugreek seed extract (1000 mg/d) with azithromycin in patients with mild to moderate acne. Fenugreek seeds were found to be inferior to azithromycin with respect to reduction in Global Acne Grading System score (14.33 vs 22.75; P = .04 [0 indicates lowest disease severity; 44 indicates greatest disease severity]) after 8 weeks of treatment. One participant discontinued the study due to gastrointestinal tract upset in the fenugreek group.

Probiotics

Given the potential role of the gut-skin axis in acne and other dermatoses, studies have explored probiotics as a potential treatment for acne.55 Lactobacillus plantarum (CJLP55), a strain of Lactobacillus isolated from kimchi, has been reported to alter cytokine production and modulate bacterial flora in the intestine as well as in the skin.56,57 Kim et al33 evaluated the efficacy of ingested CJLP55 (1.0 × 1010 colony-forming units [CFU]/d) for 12 weeks in 28 patients with mild to moderate acne vulgaris and found CJLP55 led to a greater percentage reduction ininflammatory lesion count (68.3% vs 26.2%; P = .03), total lesion count (54% vs 4.3%; P = .002), and acne grade (24.4% vs 4.6%; P = .009) than placebo.

Lactobacillus rhamnosus SP1 (LSP1) is one of the most extensively studied probiotic strains that has been shown to enhance insulin sensitivity as well as reduce lipogenesis.58 In a 12-week, double-blind trial of 20 patients, Fabbrocini et al34 demonstrated greater clinician-reported improvement with supplementation of LSP1 (3.0 × 109 CFU/d) compared with placebo (adjusted odds ratio, 28.4 [95% CI, 2.2–411.1]; P < .05).

Dias da Rocha et al31 compared an oral probiotic containing strains Lactobacillus acidophilus and Bifidobacterium lactis with placebo,both in combination with 2.5% benzoyl peroxide and 0.1% adapalene in 212 patients. After 6 months, a greater proportion of those in the probiotic group achieved an IGA of 0 or 1 than those in the placebo group (77.4% vs 64.8%; P = .03). There was no significant difference in the reduction in inflammatory (proportion of reduction, 0.841 vs 0.886) or noninflammatory lesions (proportion of reduction, 0.935 vs 0.924) between the groups (P > .05). Probiotics were well tolerated in all reported studies.

Other Nutraceuticals

Fatty Acids

The fatty acids ω-3 and ω-6 are thought to have potential utility in acne through anti-inflammatory effects.59 Jung et al35 allocated 45 participants with mild to moderate acne to receive ω-3 fatty acids (eicosapentaenoic acid and/or docosahexaenoic acid, 2000 mg/d), ω-6 fatty acids (γ-linoleic acid, 400 mg/d), or no treatment. After 10 weeks of ω-3 or ω-6 fatty acid supplementation, there was a significant reduction in the mean inflammatory (week 12: 5.8 for ω-3 fatty acids vs 6.6 for γ-linoleic acid vs 10.2 for no treatment; P < .05) and noninflammatory (week 12: 18.9 for ω-3 fatty acids vs 19.2 for γ-linoleic acid vs 22.0 for no treatment; P < .05) lesion counts as well as the mean acne grade (week 12: 1.7 for ω-3 fatty acids vs 1.8 for γ-linoleic acid vs 2.3 for no treatment; P < .05). Two patients in the ω-3 group and 1 in the γ-linoleic acid group reported mild gastrointestinal tract discomfort, which resolved spontaneously after a few days.

Cheongsangbangpoong-tang

Cheongsangbangpoong-tang is an herbal therapeutic formula that has been approved by the Korean Food and Drug Administration for clinical use in patients with acne.41 In an 8-week double-blind trial of 56 patients, Kim et al41 found that cheongsangbangpoong-tang (15 g/d) led to a greater reduction in the percentage in inflammatory lesions vs placebo (29.54% vs 1.23%; P = .002). However,there was no significant difference in IGA score change between groups (35.7% vs 28.6%; P = .78). Three participants reported digestive discomfort during treatment.

Discussion

This systematic review describes the safety and efficacy of several nutraceutical interventions for patients with acne. Given the frequent use and financial burden of nutraceuticals, it is important that physicians are aware of the available data regarding the safety and efficacy of these supplements to facilitate patient counseling about their use. Only 4 of the interventions had good-quality studies,25,26,33,41 suggesting potential effectiveness in acne (vitamin D, green tea extract, probiotics, and cheongsangbangpoong-tang). Several others had fair-quality studies,8,10,11,14–16,18,22,28,31,34,35 suggesting potential effectiveness (pantothenic acid [vitamin B5], ω-3 and ω-6 fatty acids, probiotics). Most of the nutraceutical interventions were well tolerated with limited or no adverse effects.

Although several nutraceuticals were found to have fair-to good-quality studies supporting their effectiveness, few were evaluated in more than 1 study, and most studies were of small sample size. In addition, some studies had inconsistent results depending on the outcome measure assessed. For instance, although green tea extract led to statistically significant improvements in lesion counts,26 it did not result in statistically significant improvements in quality of life, suggesting the observed lesion count differences may not be clinically meaningful to patients. While probiotics had the most studies supporting their efficacy,33,34 these were generally of very small sample size, and it is possible there could be publication bias given the large number of probiotics available on the market. In addition, there is heterogeneity among probiotic formulations, and it is not clear which are optimal for use among patients with acne. Vitamin D is likely to be a relatively low-risk option to consider, as it was dosed similarly to the recommended daily allowance in its clinical trial.60 Similarly, ω-3 and ω-6 fatty acids are reasonable options for interested patients. Cheongsangbangpoong-tang and green tea extract are commonly used in complementary and alternative medicine practices and are likely low-risk options to consider. Although pantothenic acid (vitamin B5) had fair-quality evidence to support its efficacy, the dose used in its clinical trial was substantially above the recommended daily allowance; while this dose is thought to be safe, the high dosages required raise questions about the potential risk of toxicity.61

Zinc was the most studied nutraceutical in acne; however, most studies were of poor quality and there was substantial heterogeneity in the results, with approximately half of the studies failing to demonstrate efficacy. This could be due in part to small sample sizes, short follow-up, and varying formulations and dosages. In addition, zinc was often dosed at many times the recommended daily allowance, which may increase the risk of adverse effects.

While vitamin A has been described as an alternative to isotretinoin, it often requires high doses that will have potential for the same issues as isotretinoin such as teratogenicity, neuropsychiatric disturbances, and mucocutaneous adverse effects. As a result, it is likely preferrable to use isotretinoin, which has more standardized dosing and a much stronger clinical evidence base. However, it is important to ask patients about vitamin A supplement use, given the potential for adverse effects and interactions with isotretinoin.

Limitations

This review has some limitations. Most of the studies identified were of poor quality, and most had small sample sizes. In addition, some studies had insufficient reporting to evaluate absolute effect sizes, limiting our ability to assess whether the treatment effects would be considered clinically meaningful. Given the small number of studies on each nutraceutical, there is a potential for publication bias, and there may have been other trials with negative findings that were never published, though efforts were made to identify such studies by searching sources such as the Cochrane Central Register of Controlled Trials. Finally, the heterogeneity of the study design and the nonstandardized outcome measures restricted comparisons between included studies.

Conclusion

The findings of this systematic review suggest a possible role for nutraceutical supplements in the treatment of acne. However, available evidence is limited, and larger trials are needed to better understand the efficacy of these treatments. Physicians should be prepared to discuss the evidence for nutraceuticals with patients.

Supplementary Material

Supplement

Key Points.

Question

Are oral nutraceuticals a safe and effective treatment for patients with acne?

Findings

In this systematic review of 3346 participants in 42 unique studies, 4 good-quality studies of nutraceuticals demonstrated effectiveness of vitamin D, green tea extract, probiotics, and cheongsangbangpoong-tang in the treatmento f acne. Several other fair-quality studies demonstrated effectiveness of pantothenic acid, ω-3 and ω-6 fatty acids, and probiotics.

Meaning

These findings suggest a possible role for nutraceutical supplements in the treatment of acne; physicians should engage in shared decision-making with patients regarding their use.

Funding/Support:

This study was supported by grant 1K23AR078930 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (Dr Barbieri).

Role of the Funder/Sponsor:

The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnotes

Conflict of Interest Disclosures: Dr Mostaghimi reported receiving consulting fees from Hims & Hers Health Inc, AbbVie, Concert Pharmaceuticals Inc, Digital Diagnostics, Bioniz, and Pfizer Inc; receiving royalty payments from Pfizer Inc; participating in clinical trials for Eli Lilly and Company, Concert Pharmaceuticals Inc, Incyte Corp, and Aclaris Therapeutics Inc; and receiving personal fees from Sun Pharmaceutical Industries Ltd, Equillium, ASLAN Pharmaceuticals, Boehringer Ingelheim, Figure 1, and Acom Healthcare outside the submitted work. Dr Barbieri reported receiving consulting fees from Dexcel Pharma Technologies Ltd outside the submitted work. No other disclosures were reported.

Contributor Information

Ali Shields, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Sophia Ly, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Bruna Wafae, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Yu-Feng Chang, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Priya Manjaly, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Marjorie Archila, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Christina Heinrich, Tufts University School of Medicine, Boston, Massachusetts.

Lara Drake, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

Arash Mostaghimi, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

John S. Barbieri, Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts;.

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